Cognition in Schizophrenia: Impairments, Determinants, and Functional Importance

Psychiatr Clin N Am 28 (2005) 613–633

Cognition in Schizophrenia: Impairments, Determinants, and Functional Importance Christopher R. Bowie, PhD*, Philip D. Harvey, PhD Department of Psychiatry, Mount Sinai School of Medicine, 1425 Madison Avenue, 4th Floor, Box 1230, New York, NY 10029, USA

Cognitive impairments are now recognized as one of the most ubiquitous features of schizophrenia. These impairments can be detected before the onset of symptoms that meet diagnostic criteria for schizophrenia [1], are moderate to severe in magnitude even at the time of the first break [2], and tend to persist throughout the course of the illness [3], even during episodes of remission of most other symptoms of the illness [4]. Cognitive impairments are not simply a result of other symptoms or antipsychotic treatment, because even never-medicated patients display neuropsychologic profiles similar to those with a history of antipsychotic treatment [2,5]. Moreover, with second-generation antipsychotic treatment, improvements in symptom domains seem to be relatively independent of improvements in cognitive domains [6–9], suggesting that cognitive deficits are a core feature of the illness, separable from positive and negative symptoms. In late life, a subset of patients experience a marked worsening in cognitive skills [10–12], which seems related to a concurrent decline in adaptive life skills. Assessment of cognitive functions greatly broadens the understanding of schizophrenia. It provides windows through which investigators may look into the neural bases for schizophrenia and suggests how the patient might be expected to function when faced with real-world challenges. Although cognitive tests do not localize specific neurologic dysfunction, particularly in schizophrenia, they provide insight into dysfunctional processing systems and allow detection of relative strengths and weaknesses. Cognitive This research was supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (CRB), NIMH grant # MH 63116 (PDH), and the VA VISN 3 MIRECC. * Corresponding author. E-mail address: [email protected] (C.R. Bowie). 0193-953X/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.psc.2005.05.004 psych.theclinics.com

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assessment, unlike self-reported or clinician-rated psychiatric symptoms, is based on objective performance. As a result, it can be argued that the results of cognitive testing provide valuable information on both the micro and macro levels. From an individual perspective, evaluation of functional potential can be attempted, and the success of interventions can be tracked. On a more global level, subgroups of patients can be identified based on a signature of cognitive impairments. These subgroups might share causative or course-of-illness features that allow reduction of the heterogeneity of the illness. The recognition that cognitive dysfunction is a central feature of schizophrenia has elevated its importance for both research and treatment. One of the main incentives for understanding the signature of cognitive impairment in schizophrenia is the strong relationship between cognitive performance and functional skills and functional outcome. Cognitive impairment is one of the most functionally relevant aspects of the illness. Additionally, cognitive functioning may be a vulnerability marker. Cognitive impairments are proving to be one of the symptoms within a cluster that may eventually enhance the ability to determine who is at risk of developing a psychotic disorder. Cognitive assessment may also be used as a tool to assess the beneficial and adverse effects of treatment. For example, although conventional antipsychotic medications are not directly detrimental to cognitive functions [13], anticholinergic medications, which are often needed to treat their side effects, are known to affect several cognitive functions disadvantageously, including episodic and working memory [14]. Conversely, evidence [7–9] of consistent improvements in cognitive functioning strengthens the case for the use of atypical antipsychotic medication for the treatment of schizophrenia. Several reports have related performance on cognitive tasks to specific brain regions or circuits. When compared with healthy subjects, schizophrenia patients typically manifest decreased activity in the frontal cortex and in the temporoparietal regions when performing cognitive tasks [15,16] and in the thalamus and anterior cingulate [17,18] during tests of sustained attention. The extensive work of Goldman-Rakic and colleagues [19,20] has tied working memory dysfunction in schizophrenia to the functioning of the dorsolateral prefrontal cortex. Recent work has clarified this relationship by demonstrating that even schizophrenia patients with good performance on working memory tasks are inefficient in their use of prefrontal networks [21]. Further validating the neural basis of cognitive deficits in schizophrenia are recent findings from genetic studies. Catechol-O-methyltransferase (COMT) is an enzyme that deactivates dopamine in cortical but not in subcortical regions. Several studies have demonstrated an association between COMT genotype and performance on tests of processing speed [22], verbal learning and memory [22], executive functions [23], and working memory [24]. Patients who have two valine alleles, which are associated with higher levels of COMT and greater degradation of cortical dopamine,

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perform more poorly. These studies provide opportunities for translational research in the genetic and neurobehavioral study of schizophrenia. This article reviews specific domains of cognitive deficits in schizophrenia, discusses the functional implications of these deficits, and proposes new methods for assessing the relationship between cognition and functional outcome. In so doing, it briefly reviews previous studies describing some of the well-established features of impairment in cognitive ability areas and then examines the newest data that sharpen the understanding of cognitive impairment and its relevance to other aspects of the illness.

Basic areas of impairment Despite the widespread prevalence of cognitive impairment in schizophrenia, there is considerable controversy as to whether the deficits reflect a generalized and a global neuropsychologic impairment. Although some reports [25,26] have questioned the notion that there is a specific profile of cognitive deficits in schizophrenia, there are data suggesting that there is variability among patients in level of impairment and that there is some separability across cognitive domains in terms of the overall severity of impairment. Some of this controversy is based on the breadth of the cognitive assessments performed and the extent to which current performance is compared with information about potential decline in functioning from premorbid levels. Further, the heterogeneity in schizophrenia extends to cognitive impairment, and sampling may affect the severity of measured cognitive dysfunction. The authors define each cognitive ability area (construct), describe the degree of impairment found in studies of schizophrenia patients, and discuss correlates with symptoms and functional outcome. The degree of impairment is referenced to healthy comparison samples, to normative data groups, or to the patients’ own level of functioning before the onset of illness. The authors adopt the convention that cognitive functioning is within normal limits if performance scores are within 1 SD of the normative standards, is mildly impaired if scores fall between 1 and 2 SD below the normative standards, is moderately impaired between 2 and 3 SD below the normative standards, and is severe at 3 or more SD below the normative standards. Attention The construct of attention comprises several components, including detection of relevant information, maintaining focus on those stimuli, and ignoring irrelevant competing stimuli. Early descriptions of schizophrenia [27,28] recognized attentional impairments as fundamental aspects of schizophrenia long before the advent of formal neuropsychologic testing or modern experimental psychology. Perhaps more than other aspects of

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cognition, deficits in attention may be present before the diagnosis of a psychotic condition in individuals who are genetically vulnerable to schizophrenia [29]. These impairments may further decline slightly with the onset of frank psychosis [30]. They are detectable after diagnosis at the first episode before medication treatment [31] and tend to persist even after resolution of psychotic symptoms [32,33]. The presence and severity of attentional impairments, possibly more than some other cognitive deficits, are associated with higher severity of positive symptoms [34,35]. Greater impairments in attention have been reported to be predictive of poor treatment response [36] and to identify chronic patients who do poorly when their medication dosage is reduced [37]. Impairments in vigilance, meaning the ability to sustain effort and attention while discriminating target and nontarget stimuli, are among the most widely replicated findings in the illness and are also associated with greater deficits in social problem solving and in the ability to acquire skills in training programs [38]. Because attention is the foundation for other, higher-order cognitive skills, attentional deficits are likely to limit success in many functional domains and are thus an important feature of cognitive impairment in the illness. Working memory The ability to store and manipulate information is referred to as working memory. In a hierarchical concept of cognitive functioning, working memory is the next step in processing, following selective attention and vigilance. Information that has been detected and selected for further processing is maintained in a storage system that allows further processing. Working memory differs from episodic or long-term memory in that the stimuli are not necessarily transferred to long-term storage. Working memory operations are complex and may be specialized for both the type of information (location, action, and object) and the modality of the information (verbal versus visual-spatial) [39]. Impairments in verbal working memory are common and frequently are severe in schizophrenia. Measurement of verbal working memory can include simple memory span as well as the ability to manipulate and reorganize information. Fleming and colleagues [40] demonstrated that schizophrenic patients showed marked impairments in recalling verbal information after distractor conditions, in which they had to produce competing verbal output. Patients typically manifest moderate to severe deficits on tasks that require storage, sequencing, and reproduction of verbal information [41,42]. Stone and colleagues [43] found that the moderate to severe impairments in verbal working memory that they detected could not be accounted for simply by deficits in attention. Visual working memory comprises object and spatial working memory. Park and Holzman [44] found considerable deficits in visual working

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memory using spatial delayed-response tasks. In a similar paradigm, the Dot Test [45,46], subjects must indicate, after a delay in which they read words to inhibit verbal mediation, the location of visually presented stimuli. Patients who have schizophrenia are reported to be able to perform this task within normal limits in the no-delay condition, but substantial impairments are typically found in the delay conditions. Impairments are detected in spatial working memory tasks that require even minimal additional processing (simple object alternation) [47], suggesting that these impairments are pervasive. At the same time, a recent study suggested that impairments in object working memory may be an artifact of perceptual deficits, whereas deficits in spatial working memory are consistent with impairments in the working memory system [48]. These impairments may relate to some basic deficits in processing capacity: although patients who have schizophrenia are able to complete working memory tasks at levels consistent with normal performance when the memory load is low, they nevertheless demonstrate aberrant response patterns as measured by functional MRI [49,50]. Studies that compared the relative deficits in storage versus manipulation processes in working memory have demonstrated that the impairment in the manipulation processes of working memory are considerably more severe than those observed in simple storage tasks [51]. Thus, these impairments point to basic deficiencies in processing capacity and shortterm storage in patients who have schizophrenia, even with low levels of task demands. Working memory measures may be associated with both positive and negative symptoms, although some studies have found relatively small correlations [52]. Spatial working memory has been found to be highly associated with psychomotor poverty (ie, negative symptoms) [53] and global negative symptomatology [54]. Keefe and colleagues [55,56] used a source-monitoring paradigm and found more severe delusions and hallucinations were associated with the ability to identify thoughts as selfor other-generated, which could be considered a deficit in working memory. It is likely that this aspect of working memory functions (the inability to hold information on-line for a period of time sufficient to manipulate it, attend to other information, and continuously monitor the content of consciousness) may contribute to schizophrenic symptoms ranging from disorganized behavior to delusional ideation. In addition to possibly contributing to some of the psychotic symptoms in the illness, deficits in working memory are linked to many functional domains, including impairments in occupational [57] and social behavior [58]. Patients who have working memory deficits are less likely to benefit from psychotherapy designed to teach social skills [59]. Thus, working memory impairments, possibly reflecting reductions in overall informationprocessing capacity, seem to be among the most important cognitive deficits in the illness.

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Verbal learning and memory One of the most consistent findings across studies of neurocognition in schizophrenia is the presence of moderate to severe deficits in verbal learning and memory. A comprehensive assessment of verbal learning and memory requires the subject to learn new information, either by listening to a brief story (paragraph learning) or trying to learn a list of words over a series of trials (multitrial learning). The subject is required to recall the items spontaneously after a delay without prompts or cues (delayed recall) and then to identify the target words with prompts, either from being exposed to a procedure that also contains distractors (delayed recognition) or through some cueing process (cued recall). Although schizophrenia has been conceptualized as an illness with a global cognitive deficit, substantial variability in ability exists in the verbal learning and memory domain. Overall, deficits tend to be more severe in this domain than in other areas [5,60], especially when rate of learning and delayed recall are considered. Differential impairments exist within this domain, with most patients demonstrating impaired learning rates and delayed recall but relatively intact recognition [61]. Many older schizophrenic patients who have considerable global cognitive impairment demonstrate intact recognition memory [62,63]. Although recognition memory is spared in many schizophrenia patients, some patients evidence lifelong impairments in this area, and declines in this domain in late life are predictive of global worsening in functional status [63]. One of the cognitive processes implicated in the verbal learning and recall deficit observed in schizophrenia is the inefficient use of strategies to learn new episodic information. For example, many list-learning tasks contain semantically related words from superordinate categories such as fruits or clothing. Encoding and then recalling the words according to semantic category, as opposed to the serial order in which the words were presented, is a more efficient strategy. Schizophrenia patients do not use learning strategies as efficiently as healthy subjects [64–67]. Extensive data, however, have suggested that schizophrenia patients benefit from semantic categorization to the same extent as healthy individuals. For instance, if semantic encoding can be induced incidentally, either by requiring some sort of sorting procedure [68] or having the subjects generate a story [69], patients perform consistently with normal control subjects. Thus, it seems that the semantic structure of episodic memory for schizophrenia patients is more intact than the ability to deploy these encoding strategies volitionally. Consistent with the general deficits in recall memory as compared with encoding, volitional deployment of mnemonic strategies seems to be impaired in most patients, whereas more automatically deployed retrieval techniques, such as benefiting from prompts and cues, seem to be intact. There are some reports that impaired verbal memory is moderately correlated with positive symptoms of schizophrenia [70,71]. Most research,

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however, has found correlations with negative and general symptoms of psychopathology such as depression, but not with positive symptoms [52,64,72,73]. Impairments in verbal learning and memory are among the most consistent predictors of social, adaptive, and occupational functioning in schizophrenia [74]. The ability to store information adaptively and retrieve it at a later time is crucial for social interactions, occupational performance, and completing everyday activities. Studies have demonstrated a link between impaired verbal learning and memory and skills as specific as shopping [75] and as global as problem solving [76]. In therapy, social skill acquisition is associated with verbal memory [77]. Schizophrenia patients are unlikely to benefit from many aspects of psychosocial therapy if they are unable to retain and recall information that is meant to be learned in therapeutic sessions and then generalized to the external environment. It has been shown that although intact attentional skills are important for initial job success (in the first 3 months), impairments in episodic verbal memory are likely to predict long-term vocational impairment [78]. Language skills The most commonly assessed verbal skills in schizophrenia are phonological and semantic fluency. These measures require the subject to produce words that either start with a specific letter (phonological fluency) or belong to a superordinate category, such as animals or fruits (semantic fluency). Deficits on these tests tend to be mild to moderate in schizophrenia. Schizophrenia patients do not typically reveal impairments on tests of aphasia; in fact, confrontational naming skills are preserved into late life, even in patients who have severe impairments in other domains [79]. Poor storage or loss of access to verbal information may account for verbal fluency impairments in schizophrenia [80]. Even when information is stored, however, schizophrenia patients have difficulty retrieving words with normal efficiency [81]. This inability to access the words efficiently may be caused by a reduced ability to access semantic systems systematically [82,83]. The disorganized semantic system is probably one reason schizophrenia patients do not show the typical pattern of better performance on tests of semantic fluency than of phonemic fluency [84]. Poor performance on tests of verbal fluency is associated with greater negative symptoms but not with positive symptoms [80,85]. More severe negative symptoms are associated with generation of fewer words, although poor verbal fluency is not simply an artifact of depression [86] or thought disorder [87]. The inability to organize semantically related material affects the schizophrenia patient’s production of words and results in impairments in communication. Accordingly, impairments in verbal fluency are associated

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with interpersonal skills [76] and community functions [75] and even with adaptive skills in late life [87]. Executive functioning Executive functioning has been one of the most studied neurocognitive domains in schizophrenia. It is a broad construct encompassing cognitive processes necessary for allocation of attentional resources, goal-directed behavior, and adaptation to environmental changes. Executive functioning tests are sometimes referred to as ‘‘frontal lobe’’ functions. Despite consistent findings of impairment in this domain in patients who have schizophrenia, it has been argued that deficits in these ability areas lack specificity to the frontal lobes [88,89] and lack discriminant validity from other neuropsychologic domains, such as working memory [41]. For example, even one of the most widely used measures of executive functioning in schizophrenia, the Wisconsin Card Sorting Task (WCST), can be adversely affected by impairments in working memory functions, in addition to core problem-solving impairments. Executive functioning is the ability to solve problems, employ abstract thinking, and coordinate other cognitive skills such as working memory and attentional systems. Although the the WCST is the test most commonly used to assess concept formation and set shifting, and deficits on this test have been well replicated in schizophrenia, executive functioning is actually a multifaceted construct (see ref. [90] for a detailed discussion). When the WCST is used as the reference measure of executive functioning, moderate to severe impairments are detected in several different domains, including the number of conceptual categories attained [91], total efficiency, and perseverative tendencies [92,93]. Other ways to measure executive functioning include tests that require more planning and less interactive reaction to ongoing environmental events. Planning abilities can be measured with tasks that require the subject to reach a goal efficiently, such as the various Tower tasks. These tasks have in common the demand that the subject organize responses efficiently, using as few moves as possible to solve problems of varying complexity. Patients who have schizophrenia perform poorly on these tests [94–96]. Studies of the relationship between neurocognitive domains and functional status consistently identify limitations in executive functioning as one of the important predictors of deficits in basic self-care skills [97], social/interpersonal skills [97], community skills [75,97], and occupational functioning [97–100]. Patients who have executive dysfunction are less likely to use treatment services [101]. Furthermore, even when patients do use treatment services, engagement within therapy sessions [102], therapeutic alliance [103], and compliance with prescribed medication [104,105] are inversely correlated with executive dysfunction. Thus, given the role of executive dysfunction in treatment compliance and participation, it is not

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surprising that it is related to length of hospitalization [106] and a poorer course of illness. Patients who have executive dysfunction may have less contact with family members and less financial support [107], further increasing their risk for poor outcome. Social cognition The concept of social cognition as an important and functionally relevant deficit in schizophrenia has gained support recently [108]. This construct is defined broadly as a set of cognitive abilities that allows people to perceive and make sense of their surroundings and the thoughts and actions of themselves and others. In contrast to aspects of cognitive functions that are often referred to as ‘‘cold cognition,’’ social cognition refers to the ability to perceive and react to emotional experiences on one’s own part and to interpret the emotional displays of other individuals. Social cognition typically is measured with instruments that evaluate the ability to perceive, interpret, and respond in accordance to the emotions and intents of others, while considering one’s own emotional reactions as well. This area of research is less developed than aspects of neurocognition. One of the difficulties in determining the severity of social cognitive deficits in schizophrenia is that the previous studies of social cognition have not adopted a psychometric approach to test development. Many of the tests previously developed lack variance in groups of healthy people. Although on most neurocognitive tests the performance of healthy individuals varies considerably because of attempts to develop tests that elicit normal distributions of test performance, several attempts to measure the social cognitive deficits in individuals who have schizophrenia may have been handicapped by ceiling effects. In fact, some validity studies of social cognitive measures have been published without reference to a healthy control group [109], raising some concern about the ability to these measures to detect discriminating deficits. Some concerns have been raised about whether some widely reported deficits in schizophrenia, such as affect perception, have been unduly influenced by the psychometric properties of the measures [110]. Still, the construct of social cognition has considerable potential importance for functional outcome in schizophrenia, if measurement issues are resolved. The reason for the potential functional relevance of this cognitive ability is transparent: the inability to perceive, process, and organize social information accurately is likely to affect one’s social functioning adversely. Patients who have schizophrenia show deficits in the ability to recognize emotions based on facial expressions or tone of voice; these deficits have been linked to failures in perceptual processing, attention, and verbal memory [111,112] It is becoming increasingly clear that social cognition is a separable factor from schizophrenic symptoms [113]. Social cognition may also serve as a mediating factor in the relationship between neurocognition

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and social functioning [114]. That is, although neurocognitive functions are necessary for success in many functional domains, these skills may not be of functional use in the absence of other skills, such as the ability to identify social cues. Thus, social cognitive deficits may add incremental predictive power to the understanding of functional impairments in schizophrenia [115].

Additional considerations Substance abuse Although substance abuse exacerbates impairment in many neurocognitive domains [116–118], its effects are most pronounced on learning and memory. In both cocaine-abusing [116] and alcohol-abusing [118] patients who have schizophrenia, the rate of acquisition of information across learning trials and the proportion of words recalled after delay are similar to those of schizophrenic patients who do not abuse substances, but the overall number of words learned and recalled is fewer. This phenomenon may reflect a deficit in processing capacity or the amount of information available to be stored, rather than a direct effect on the ability to benefit from learning over trials or to remember information that was stored. It is estimated that as many as 60% of schizophrenics meet diagnostic criteria for a substance-use disorderdexcluding nicotine and caffeinedat some point in their lives [119]. Despite the widespread prevalence of substance abuse in schizophrenia, most studies still use substance abuse as an exclusion criterion. Although it clearly is important to understand the impact of substance use on cognition in schizophrenia and on other aspects of the illness, one of the issues in this area is the tendency for patients who have schizophrenia to abuse more than one substance. Polysubstance abuse makes it difficult to identify specific effects; however, if polysubstance abuse is the norm, then future research would be wise to focus on the multiplicative or additive adverse effects of abuse of these substances. To perform clinically relevant research, researchers should consider controlling for substance abuse at the level of data analysis rather than excluding such patients at the level of recruitment; otherwise, findings will generalize to less than half the population of patients who have schizophrenia. Course of cognitive deficits over the lifespan Cognitive deficits are detectable before the onset of frank psychosis and when patients first meet criteria for schizophrenia. These deficits are present in multiple areas of cognitive ability, and deficits across these areas typically range from moderate to severe as compared with healthy individuals. With the onset of psychosis, a modest decline in general intellectual functions has

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been reported [30], and impairment in adulthood is greater than estimates of premorbid cognitive functioning [120]. Although inter- and intraindividual variability exists, cognitive deficits tend to persist from the time of the first episode into middle adulthood without significant change in their topography or severity over short follow-up intervals [3,121,122]. These findings have been interpreted as evidence for a static course throughout the illness [123]. Recent work, however, suggests that the course is more dynamic, at least for a subset of patients. When patients who have schizophrenia are studied into late life, declines in cognitive functions in some patients area as severe as seen in dementia [10–12], although post-mortem analyses of these subjects do not reveal pathology similar to known causes of late-life dementias including Alzheimer’s disease [124]. This cognitive decline is not accounted for by medical illness [125]. The course of this decline [10–12] and its cross-sectional profile [122,126] are quite different from that seen in Alzheimer’s disease. It is likely that the substantial global cognitive decline observed in the subjects of the Harvey and Friedman studies [10–12,125] are atypical of schizophrenia and apply only to those with a particularly adverse course of illness or a chronic course of treatmentrefractory psychosis. More recent work from multiple laboratories has confirmed a dynamic course of cortical changes beginning even at the time of the first episode [127], with even more drastic changes seen in cases with childhood onset [128] or in middle-aged patients who have refractory psychotic symptoms [129]. These findings suggest that in many patients who have schizophrenia, an active process of cortical change, possibly exacerbated in cases with poorly responsive psychotic symptoms [130], may be present. Thus, cognitive decline may be common in aging schizophrenic patients, with a profile of vulnerability to this decline that is only beginning to be discovered. In older ambulatory patients who have schizophrenia, cognitive declines may be restricted to complex cognitive domains such as executive function [131] and complex information processing [132]. Identification of the specificity and predictors of cognitive decline with aging might lead to reduction in disability as well as understanding of the neuropathologic processes associated with aging in schizophrenia. Assessment methods With a new priority on measuring cognition in schizophrenia, new concerns have emerged regarding assessment of cognitive functioning. Assessments must be broad enough to capture relevant deficits but retain feasibility. Although some abbreviated instruments, such as the Repeatable Battery for the Assessment of Neuropsychological Status, have adequate psychometric properties, they are not designed specifically to be sensitive to the cognitive impairments of schizophrenia and do not capture important domains such as working memory and executive functioning. Several

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different abbreviated cognitive assessments have been proposed, including the Brief Assessment of Cognition in Schizophrenia [133] and the Brief Cognitive Assessment [134]. For all abbreviated assessment instruments, more data are required to ensure that these assessments reliably capture the important features of cognitive impairment in schizophrenia. The evolving understanding of the relationships between cognitive dysfunction and functional outcome Despite adequate control of psychotic symptoms achieved in many patients with the use of antipsychotic medications, less progress has been made in improving functional outcome in schizophrenia since the advent of conventional antipsychotic treatments [135]. An open question in studies of the functional relevance of cognition is whether the relationship is better understood in terms of global cognitive impairment or by examining specific ability areas as predictors of outcome. Not unexpectedly, many neurocognitive variables are highly correlated with each other and share variance in predicting functional domains. Dickinson and colleagues [136] found that among the four Wechsler Adult Intelligence Scale (WAIS) factors, working memory and processing speed accounted for community functioning, but the addition of positive and negative symptoms substantially increased predictive power. Only processing speed survived as a predictor of functional status after controlling for the other WAIS factors. IQ scores, however, are not a comprehensive neuropsychologic assessment; they do not measure executive functions, verbal learning, or episodic memory, all of which are strong predictors of social and adaptive functions in schizophrenia patients. Evans and colleagues [137] examined seven neurocognitive domains and three symptom domains as correlates of two levels of adaptive functions: basic activities of daily living (eg, eating) and instrumental activities of living (eg, shopping). All seven neurocognitive domains were associated with both aspects of functional skills. Global scores on cognition accounted for most of the variance in both functional skills, even after controlling for negative symptoms. None of the neurocognitive domains were differentially more predictive of functional skills. These data suggest that different cognitive domains have similar relationships to outcome. Prediction of more discrete functional competencies than were used in the study by Evans and colleagues would be necessary to reveal independent neurocognitive predictors [38,74,138]. Although there is general agreement that neurocognition is a strong predictor of social and adaptive functions, there is no consensus on exactly how to measure these functional domains, particularly for treatment studies. Recent developments include performance-based measures of functional skills that can be used in the laboratory setting. The University of California–San Diego Performance-Based Skills Assessment Battery [139]

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is a laboratory-based measure with adequate psychometric characteristics. Valid assessment of skills in the laboratory may only approximate real world functions, however. Furthermore, the source of information regarding real-world functioning may be critical. Jin and colleagues [140] found an association between self-reported depression and self-reported instrumental functional skills. McKibbin and colleagues [141] found depression, but neither cognition nor or performance-based functional skills, to be associated with self-reported disability in schizophrenia outpatients. Work with other neuropsychiatric groups, such as HIV patients [142], also found a role for depressive symptoms in mediating the relationship between neurocognition and real-world functional skills. Recently, the authors found that the relationship between neurocognition and real-world functional performance was mediated by performance-based assessments of functional skills. Treatment of cognitive dysfunction in schizophrenia Although conventional antipsychotic medications have little effect on neurocognitive functions in schizophrenia, second-generation antipsychotic medications do produce cognitive improvements in some patients [143]. Most changes are modest, particularly given the degree of impairment typically observed in schizophrenia. One of the issues in these studies may be duration of treatment, because most are only 6 to 8 weeks in duration. A recent study found that some patients treated with he atypical antipsychotics olanzapine or ziprasidone benefit to a degree associated with normalization of cognitive performance [144], but these patients were treated for 6 months and enrolled in the study only if they were substantially clinically responsive to short-term treatment. This study highlights the importance of studying the clinical meaningfulness of cognitive change with pharmacotherapy. The cognitive benefits of switching to second-generation antipsychotic medication have not translated into simultaneous functional improvement [145], at least for self-reported measures, although improvements in social cognition and social adjustment may be revealed over time with psychosocial interventions [146]. It will be important to examine whether functional deficits lag behind cognitive improvements that result from antipsychotic medication or whether behavioral or other pharmacotherapy interventions are needed. The findings of modest cognitive improvements with second-generation antipsychotic medication offer promise but do not resolve cognitive dysfunction in schizophrenia. Behavioral strategies for cognitive improvement are effective in improving neurocognitive deficits, demonstrate durability over time [147,148], and potentially normalize performance [149]. Strategies that help patients who have schizophrenia compensate for their cognitive deficits may lead to functional improvements [150]. Because treatments with second-generation antipsychotic medications may produce modest

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improvements in neurocognitive functions, they may provide a platform for behavioral interventions that stimulate and extend improvement and facilitate functional recovery. Summary Recent findings support and add to earlier findings of cognitive dysfunction in schizophrenia. Deficits across neurocognitive domains such as attention, working memory, language skills, and executive functioning tend to be moderate, with the most pronounced deficits found in verbal learning and memory. All these neurocognitive domains are related to adaptive and social skills, with executive functions and verbal learning and memory showing more variance across more domains than other neurocognitive variables. Negative symptoms and neurocognitive domains, although correlated, are distinct and have differential pathways of change with treatment. General psychopathology symptoms, such as depression and anxiety, may become important treatment targets as strategies are developed for translating cognitive enhancement to real-world functional performance. References [1] Davidson M, Reichenberg A, Rabinowitz J, et al. Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry 1999;156(9): 1328–35. [2] Bilder RM, Goldman RS, Robinson D, et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 2000; 157(4):549–59. [3] Heaton RK, Gladsjo JA, Palmer BW, et al. Stability and course of neuropsychological deficits in schizophrenia. Arch Gen Psychiatry 2001;58(1):24–32. [4] Addington J, Addington D, Gasbarre L. Distractibility and symptoms in schizophrenia. J Psychiatry Neurosci 1997;22(3):180–4. [5] Saykin AJ, Shtasel DL, Gur RE, et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry 1994;51(2):124–31. [6] Addington J, Addington D. Neurocognitive functioning in schizophrenia: a trial of risperidone versus haloperidol. Can J Psychiatry 1997;42(9):983. [7] Harvey PD, Siu CO, Romano S. Randomized, controlled, double-blind, multicenter comparison of the cognitive effects of ziprasidone versus olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Psychopharmacology (Berl) 2004;172(3): 324–32. [8] Harvey PD, Green MF, McGurk SR, et al. Changes in cognitive functioning with risperidone and olanzapine treatment: a large-scale, double-blind, randomized study. Psychopharmacology (Berl) 2003;169(3–4):404–11. [9] Keefe RS, Seidman LJ, Christensen BK, et al. Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 2004;161(6):985–95. [10] Harvey PD, Parrella M, White L, et al. Convergence of cognitive and adaptive decline in late-life schizophrenia. Schizophr Res 1999;35(1):77–84.

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